A5013719000- PI3K/AKT/mTOR signaling in cancer
- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Genetic Syndromes and Imprinting
- Cancer-related Molecular Pathways
- Autophagy in Disease and Therapy
- Erythrocyte Function and Pathophysiology
- Biomedical Research and Pathophysiology
- Epigenetics and DNA Methylation
- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- Lung Cancer Treatments and Mutations
- CRISPR and Genetic Engineering
- Cancer Genomics and Diagnostics
- Retinal Development and Disorders
- Immune Cell Function and Interaction
- RNA modifications and cancer
- Genetic and Kidney Cyst Diseases
- ATP Synthase and ATPases Research
- Mitochondrial Function and Pathology
- Cancer-related gene regulation
- T-cell and B-cell Immunology
- Neuropeptides and Animal Physiology
- Melanoma and MAPK Pathways
- Cancer, Hypoxia, and Metabolism
University College London
2015-2024
Cancer Institute (WIA)
2019-2024
CRUK Lung Cancer Centre of Excellence
2017-2024
Institut de Génomique Fonctionnelle
2017
Queen Mary University of London
2010-2014
Cancer Research Institute
2004-2007
University of California, San Francisco
2004-2007
Centre National de la Recherche Scientifique
1996-2001
Inserm
1996-2001
Institut Curie
1998
Pituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACAP-38 are neuropeptides of the vasoactive intestinal peptide/secretin/glucagon family. We previously described alternative splicing region encoding third intracellular loop PACAP receptor generating six isoforms with differential signal transduction properties (Spengler, D., Waeber, C., Pantaloni, Holsboer, F., Bockaert, J., Seeburg, P. H., Journot, L. (1993) Nature 365, 170-175). In addition, we demonstrated that potencies...
We previously reported the identification of mZac, a novel mouse zinc finger protein that shared with p53 ability to regulate concomitantly apoptosis and cell cycle progression. describe here isolation, chromosomal localization, functional in vitro characterization its human homolog. hZAC is widely expressed reveals transactivation DNA-binding activity. inhibits tumor growth through induction apoptotic death G 1 arrest. Thus hZAC, like counterpart, displays antiproliferative properties...
Abstract Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact systemic inhibition kinase activity not completely understood. Here we show heterozygous kinase-dead mice are healthy and display robustly enhanced insulin sensitivity glucose tolerance, phenotypes mimicked by selective inhibitor in wild-type mice. underlying mechanism sensitization multifactorial through canonical...
In contrast to the class I phosphoinositide 3-kinases (PI3Ks), organismal roles of kinase activity II PI3Ks are less clear. Here, we report that PI3K-C2β kinase-dead mice viable and healthy but display an unanticipated enhanced insulin sensitivity glucose tolerance, as well protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic inhibition selectively enhances signaling only in metabolic tissues. primary hepatocyte model, basal PI3P...
PLAGL1/ZAC1 undergoes parental genomic imprinting, is paternally expressed, and a member of the imprinted gene network (IGN). It encodes zinc finger transcription factor with anti-proliferative activity candidate tumor suppressor on 6q24 whose expression frequently lost in various neoplasms. Conversely, gain PLAGL1 function responsible for transient neonatal diabetes mellitus, rare genetic disease that results from defective pancreas development. In present work, we showed Plagl1...
Mutations of the mitochondrial genome (mtDNA) cause a range profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While level broadly correlates with disease severity, relationships between specific mutations, heteroplasmy, phenotype severity poorly understood. We have carried out extensive bioenergetic, metabolomic RNAseq studies on heteroplasmic patient-derived cells...
The tuberous sclerosis complex (TSC) proteins TSC1 and TSC2 regulate protein translation by inhibiting the serine/threonine kinase mTORC1 (for mammalian target of rapamycin 1). However, how control overall synthesis specific mRNAs in response to different mitogenic nutritional stimuli is largely unknown. We show here that serum withdrawal inhibits signaling, causes disassembly initiation complexes, mRNA redistribution from polysomes subpolysomes wild-type mouse embryo fibroblasts (MEFs). In...
ZAC is a recently isolated zinc finger protein that induces apoptosis and cellcycle arrest. The corresponding gene imprinted maternally through an unknown mechanism maps to 6q24–q25, within the minimal interval harboring responsible for transient neonatal diabetes mellitus (TNDM) tumor suppressor involved in breast cancer. Because of its functional properties, imprinting status, expression pattern mammary cell lines tumors,ZAC best candidate so far both disease conditions. In present work,...
Focal adhesions are multifunctional organelles that couple cell-matrix adhesion to cytoskeletal force transmission and signaling steer cell migration collective behavior. Whereas proteomic changes at focal well understood, little is known about lipids in dynamics. Through the characterization of cells from mice with a kinase-inactivating point mutation class II PI3K-C2β, we find generation phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) membrane lipid promotes disassembly response...
RNAi (RNA interference) and ASO (antisense oligonucleotide) technologies are the most commonly used approaches for silencing gene expression. However, specificity of such powerful tools is an important factor to correctly interpret biological consequences silencing. In present study, we examined effects acute loss Ser/Thr kinase PDK1 (3-phosphoinositide-dependent 1) expression using RNAi, compared, first time, these two techniques Affymetrix microarrays. We show that both ASO- siRNA (small...
Phosphoproteomic techniques are contributing to our understanding of how signaling pathways interact and regulate biological processes. This technology is also being used characterize networks remodeled during disease progression identify biomarkers pathway activity responses cancer therapy. A potential caveat in these studies that phosphorylation a very dynamic modification can substantially change the course an experiment or retrieval processing cellular samples. Here, we investigated...
Recycling is a limiting step for receptor-mediated endocytosis. We first report three in vitro or vivo evidences that class III PI3K/VPS34 the key PI3K isoform regulating apical recycling. A substractive approach, comparing Opossum Kidney (OK) cells pan-class I/II/III inhibitor (LY294002) with I/II (ZSTK474), suggested inhibition induced selective endosome swelling and sequestration of endocytic receptor, megalin/LRP-2, causing surface down-regulation. GFP-(FYVE)x2 overexpression to...
Abstract Kidney proximal tubular cells (PTCs) are highly specialized for ultrafiltrate reabsorption and serve as paradigm of apical epithelial differentiation. Vps34/PI3-kinase type III (PI3KC3) regulates endosomal dynamics, macroautophagy lysosomal function. However, its in vivo role PTCs has not been evaluated. Conditional deletion Vps34/PI3KC3 by Pax8-Cre resulted early (P7) PTC dysfunction, manifested Fanconi-like syndrome, followed kidney failure (P14) death. By confocal microscopy,...
While the class I phosphoinositide 3-kinases (PI3Ks) are well-documented positive regulators of metabolism, involvement II PI3K isoforms (PI3K-C2α, -C2β and -C2γ) in metabolic regulation is just emerging. Organismal inactivation PI3K-C2β increases insulin signalling sensitivity, whereas PI3K-C2γ has a negative impact. In contrast, role PI3K-C2α organismal metabolism remains unexplored. this study, we investigated whether kinase affects glucose mice. We have generated characterised mouse line...
Abstract Primary cilia are antenna-like organelles which sense extracellular cues and act as signalling hubs. Cilia dysfunction causes a heterogeneous group of disorders known ciliopathy syndromes affecting most organs. disassembly, the process by cells lose their cilium, is poorly understood but frequently observed in disease upon cell transformation. Here, we uncover role for PI3Kα enzyme disassembly. Genetic PI3Kα-hyperactivation, PIK3CA -related overgrowth spectrum (PROS) cancer, induced...
Regulatory T (Treg) cells are essential for the maintenance of immunological tolerance, yet molecular components required their and effector functions remain incompletely defined. Inactivation VPS34 in Treg led to an early, lethal phenotype, with massive cell activation inflammation, like mice lacking completely. However, VPS34-deficient developed normally, populated peripheral lymphoid organs effectively supressed conventional